Process for producing medicinal composition of basic hydrophobic medicinal compound

ABSTRACT

The present invention provides a method for preparation of a pharmaceutical composition which comprises suspending a hydrophobic medical compound without generating foams. 
     The present inventors have directed attention to properties of a hydrophobic medical compound and found a method for preparation of a pharmaceutical composition which comprises suspending and dispersing a basic hydrophobic medical compound, and neutralizing with a basic aqueous solution.

This application is a 371 of PCT/JP00/02213 filed Apr. 6, 2000.

TECHNICAL FIELD

This invention relates to a method for preparation of a pharmaceuticalcomposition comprising a basic hydrophobic medical compound.

BACKGROUND ART

In preparation of pharmaceutical compositions, a spray dry method isoften used. Japanese Patent Publication Kokai 1988-20302 discloses aspray dry method which comprises spraying an acidic solution ofchitosan. Japanese Patent Publication Kokai 1988-210101 discloses amethod which comprises spraying an acidic solution of chitosan followedby neutralization with a basic solution. These methods are used forreducing or adjusting the particle size of chitosan and characterized inusing an acidic solution of chitosan. These documents do not disclose orindicate the utility and dispersion of a suspension.

In preparation of pharmaceutical compositions comprising a hydrophobicmedical compounds, an aqueous suspension must be prepared when a spraydry method is used. The preparation of the above suspension is oftendifficult because a direct addition of the hydrophobic compound to watergenerates micro foams to form a foaming layer. The foaming layer is noteasily degassed due to its stability.

As a method for suspending a hydrophobic medical compound withoutgenerating foams, the following methods are known; (1) a method forsuspending under reduced pressure, and (2) a method using organicsolvents.

The above method (1) requires special equipment. The above method (2) isaccompanied with problems such as the danger of explosion and theresidual solvents.

DISCLOSURE OF INVENTION

The present invention provides a method for preparation of apharmaceutical composition, which comprises suspending a hydrophobicmedical compound without forming foams. The present method does notrequire any special equipment and excludes the conventional problemsrelating to the danger of explosion and the residual solvents.

The present inventors have researched for developing a method forpreparation of a pharmaceutical composition, which is characterized bysuspending and dispersing a hydrophobic medical compound without formingfoams, and have found that when a hydrophobic medical compound is basic,the formation of foams can be suppressed by the suspending anddispersing the compound in an acidic solution, whereby usual methods forstirring can be used for suspending and dispersing.

The present inventors have further found that the above obtained acidicsuspension of a basic hydrophobic medical compound does not form afoaming layer even upon neutralization with a basic aqueous solution.The obtained suspension is neutral and so can be used for preparation ofpharmaceutical compositions such as granulation process without rustingpharmaceutical equipment.

Thus, in the present invention, the generation of micro foams andformation of a foaming layer, which occur in the direct addition of abasic hydrophobic medical compound to water (e.g., purified water), canbe suppressed by suspending and dispersing the basic hydrophobic medicalcompound in an acidic solution, followed by neutralization with a basicaqueous solution.

A spray dry method which comprises spraying and drying a suspension of acompound in atmosphere at high temperature to prepare a dried granule,requires preparation of a suspension of which the suspensibility anddispersibility is improved. The suspension of the present invention,therefore, is useful.

This present invention provides:

-   1) a method for preparation of a pharmaceutical composition which    comprises a process of suspending and dispersing a basic hydrophobic    medical compound in an acidic aqueous solution and a process of    neutralizing the suspension obtained through said suspending and    dispersing process with a basic aqueous solution,-   2) a method for preparation of a pharmaceutical composition which    comprises a process of suspending and dispersing a basic hydrophobic    medical compound in an acidic aqueous solution, a process of    neutralizing the suspension obtained through said suspending and    dispersing process with a basic aqueous solution, and a process of    spraying and drying the suspension neutralized through said    neutralizing process in atmosphere at high temperature,-   3) the method for preparation of a pharmaceutical composition    according to the above 1) or 2) which is carried out for the purpose    of suppressing a formation of a foaming layer,-   4) the method for preparation of a pharmaceutical composition    according to the above 1) or 2) which is carried out for the purpose    of improving the suspensibility and dispersibility,-   5) the method for preparation of a pharmaceutical composition    according to any one of the above 1) to 4) wherein the acidic    aqueous solution is an aqueous solution of malic acid, citric acid    or phosphoric acid,-   6) the method for preparation of a pharmaceutical composition    according to any one of the above 1) to 5) wherein the basic aqueous    solution is an aqueous solution of sodium hydroxide or potassium    hydroxide,-   7) the method for preparation of a pharmaceutical composition    according to any one of the above 1) to 6) wherein the basic    hydrophobic medical compound is a pyridine derivative, an imidazole    derivative or an alkylamine derivative,-   8) the method for preparation of a pharmaceutical composition    according to any one of the above 1) to 7) wherein the basic    hydrophobic medical compound is    5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl    carbamate,-   9) the method for preparation of a pharmaceutical composition    according to any one of the above 1) to 8) wherein the    pharmaceutical composition is an suspension, a dry granule, a tablet    or a dry syrup, and-   10) a pharmaceutical composition which is prepared by a method    according to any one of the above 1) to 9).

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an example of the step of the present invention.

FIG. 2 shows an example of the step of the present invention formanufacturing tablets.

FIG. 3 shows an example of the step of the present invention formanufacturing a pediatric dry syrup.

FIG. 4 shows dissolution profile of a pharmaceutical composition of thepresent invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a method for preparation of apharmaceutical composition which comprises a process of suspending anddispersing a basic hydrophobic medical compound in an acidic aqueoussolution, a process of neutralizing the obtained suspension with a basicaqueous solution, and a process of spraying and drying the obtainedsuspension in atmosphere at high temperature. For example, the presentinvention includes the following steps, some of which are shown in FIG.1.

-   (A) An acidic solution is prepared by adding various acids to water    such as purified water.-   (B) A basic hydrophobic medical compound is added and dispersed in    an acidic solution obtained in the above (A).-   (C) A suspension is prepared by neutralizing the suspension obtained    in the above (B) with a basic solution.-   (D) A dried granule is prepared by spraying and drying the    suspension obtained in the above (C) in atmosphere at high    temperature.-   (E) A pharmaceutical composition is prepared by mixing the dried    granule obtained in the above (D) with various excipients.

In the procedure (A), an acid may be added to water, and vice versa.

A acid to be used in the present invention includes a generally usedacid such as an organic acid (e.g, malic acid, citric acid, lactic acid,acetic acid or the like) or an inorganic acid (e.g., hydrochloric acid,phosphoric acid or the like). Preferred is malic acid, citric acid,phosphoric acid or the like.

In order to dissolve a basic hydrophobic medical compound in water, onemole equivalent of an acid to the compound is generally required to forma salt. In the present invention, an acidic aqueous solution is used forimproving the suspensibility and dispersibility, not for dissolving abasic hydrophobic compound. Therefore, the amount of an acid in anacidic aqueous solution is 0.01 to 0.5 mole equivalent, preferably 0.04to 0.2 mole equivalent to a basic hydrophobic medical compound.

In the procedure (B), a basic hydrophobic medical compound is added toan acidic solution obtained in the procedure (A), whereby preventing asuspension from forming a foaming layer, which is formed when a compoundis added to a neutral solution, and giving a suspension with a highdispersibility. The control of the amount of an acid in the procedure(A) can well lead to the preparation of a suspension, not a solution.

A basic hydrophobic medical compound in the present invention includes ahydrophobic organic compound exhibiting basicity and having apharmaceutical activity, and preferred is pyridine derivatives,imidazole derivatives or alkylamine derivatives. Pyridine derivativesinclude hydrophobic organic compounds having a pyridine ring. Imidazolederivatives include hydrophobic organic compounds having an imidazolering. Preferred are hydrophobic organic compounds having an imidazolering and a pyridine ring. Alkylamine derivatives include hydrophobicorganic compounds having an alkylamino group.

Examples of imidazole derivatives include a compound of the formula (I):

wherein R¹ is alkyl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl, R² is carbamoyloxyalkyl, hydroxyalkyl,aminoalkyl, acetoxyalkyl or cyanoalkyl, R³ is ethyl or isopropyl, R⁴ isalkyl or halogen, and X is —S— or —CH₂—. These compounds are useful asanti HIV agents and disclosed in WO96/10019.

Alkyl includes C₁-C₄ straight or branched alkyl, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Aralkyl includes the above alkyl substituted with aryl such as phenyl,naphthyl or the like, for example, benzyl, phenethyl, phenylpropyl,naphthylmethyl, naphthylethyl or the like.

Heteroaralkyl includes the above alkyl substituted with heteroaryl suchas pyridyl, for example, picolyl, pyridylethyl, pyridylpropyl or thelike.

Carbamoyloxyalkyl, hydroxyalkyl, aminoalkyl, acetoxyalkyl and cyanoalkylincludes the above alkyl substituted with carbamoyloxy, hydroxy, amino,acetoxy and cyano, respectively, for examples, carbamoyloxymethyl,carbamoyloxyethyl, carbamoyloxypropyl, hydroxymethyl, hydroxyethyl,hydroxypropyl, aminomethyl, acetoxymethyl, cyanomethyl, cyanoethyl orthe like. Preferred is carbamoyloxymethyl, hydroxymethyl or aminomethyl.

The compound of the formula (I) wherein R¹ is optionally substitutedpicolyl belongs to imidazole derivatives as well as pyridinederivatives. The examples include compound (I-1),5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-0.2-ylmethylcarbamate or the like.

Examples of pyridine derivatives include nicotinamide, nikethamide,isoniazid, nialamide, ethionamide, prothionamide or the like.

Examples of alkyl amine derivatives include pindolol, noscapine or thelike.

The structures of these compounds are shown below.

In the procedure (C), the rusty of equipment can be prevented byneutralizing the suspension obtained in (B) with a basic aqueoussolution. Though thus obtained suspension does not form a foaming layereven under stirring in spite of the neutrality. The present invention,therefore, can provide a suspension exhibiting the high suspensibilityand dispersibility.

A basic solution includes a solution in which a general base isdissolved. A base includes, for example, sodium hydroxide, potassiumhydroxide, sodium hydrogencarbonate or the like. Preferred is sodiumhydroxide or potassium hydroxide.

In the step (D), a dried granule can be prepared. A generally knownspray dry method and equipment can be used.

In the step (E), various pharmaceutical compositions such as a tablet, adry syrup or the like can be prepared. The pharmaceutical compositionmay include excipients, because the present invention is characterizedby the above steps (A) to (E).

A pharmaceutical composition includes a preparing composition and aprepared composition, for example, a suspension, a granule, a tablet, acapsule, a dry syrup (e.g, pediatric dry syrup) or the like. Thepharmaceutical composition of the present invention includes ansuspension obtained in (C) and a granule obtained in (D) as well as atablet, a capsule, a dry syrup or the like prepared by using them. Apharmaceutical composition (e.g, a tablet, a dry syrup (e.g, pediatricdry syrup)) prepared through the present invention exhibits improvementof dissolution rate, suspendabitily, dispersibility and stability, ascompared with a pharmaceutical composition prepared through directaddition of a hydrophobic compound to water.

As described above, a spray dry method can not be used because offorming a foaming layer when a compound is basic and hydrophobic. Thepresent invention enables a pharmaceutical composition to be preparedthrough a spray dry method even when a compound is basic andhydrophobic. A pharmaceutical composition (e.g., a tablet, a dry syrup)prepared through the present invention exhibits improvement ofbioavailability, as compared with a pharmaceutical composition preparedwithout using a spray dry method (e.g., a pharmaceutical compositionprepared through a general granulation method).

The steps of a tablet and a dry syrup (a pediatric dry syrup) are shownin FIGS. 2 and 3, respectively. The terms to be used in Figure show thefollowing meanings. (PVP K30: polyvinylpyrrolidone K30, Ac-Di-Sol:Crosscarmellose Sodium, Aerosil: light anhydrous silicic acid).

FIG. 2 shows a flowchart for tablet manufacturing. To a solutioncontaining purified water, various acids and PVP K30 was added andsuspended a basic hydrophobic medical compound. Second, a suspension wasprepared by neutralizing the above suspension with a NaOH aqueoussolution. A dried granule was prepared by spraying and drying thesuspension. A lubricated granule was prepared by adding StMg andAc-Di-Sol thereto. A tablet was prepared by tableting the above obtainedlubricated granule.

FIG. 3 shows a flowchart for dry syrup manufacturing. To a solutioncontaining purified water, malic acid and PVP K30 was added andsuspended a basic hydrophobic medical compound. Second, a suspension wasprepared by neutralizing the above suspension with a NaOH aqueoussolution. A dry granule was prepared by spraying and drying thesuspension. A dry syrup was prepared by mixing the above dried granulewith a silicon resin adsorbent powder prepared from aerosil and siliconresin, sodium benzoate, powdered sucrose and xanthan gum.

PVP K30 is used as a binder. A binder is not limited to PVP K30. Anywater-soluble binder, for example, HPC, Dextrin can be used.

Ac-Di-Sol is used as a disintegrator. Any disintegrator, for example,LHPC, CMC-Ca, can be used.

StMg is used as a lubricant. Xanthan gum is used as a thickener. Aerosilis used as an absorbent. Silicon resin is used as a defoaming agent anda suspending agent. Powdered sugar is used as a sweetener and aflavoring agent. Each agent is not limited thereto.

EXAMPLE

Examples of the present invention are shown below. An acidic solution tobe used in the following examples is a solution of malic acid, citricacid and phosphoric acid. A basic aqueous solution to be used in thefollowing examples is a solution of NaOH. A basic hydrophobic compoundto be used in the following examples is compound (I-1), pindolol andnoscapine. The compound (I-1) is5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbamate.

Example 1 A Method for Preparation of a Tablet of Compound (I-1)

100 g of PVP K30 was dissolved to 1600 g of purified water. Theseaqueous solution were acidified by DL-Malic acid. The compound (I-1) wasdispersed in the acidic solution under stirring. The suspension wasneutralized with 230 g of 13% NaOH aqueous solution.

A dried granule was prepared by spraying and drying the obtainedsuspension with L-8 type of spray dryer. 700 g of the granule wasblended with 21 g of Ac-Di-Sol and 28 g of StMg to give a lubricatedgranule. A tablet (weight: 631.3 mg, thickness: 5.0 mm per a tablet) wasprepared by using rotary tabletting machine (LIBRA 836BK-AWCZ) equippedwith couplet type of pestle (18.5×7.9 mm).

The contents of the obtained tablet were shown in Table 1.

TABLE 1 The contents of a tablet prepared by a spray dry method addingan acid. Weight per a tablet Compound (I-1) 500.0 Mg PVP K30 50.0DL-malic acid 25.0 Sodium hydroxide 15.0 StMg 23.6 Ac-Di-Sol 17.7 Total631.3 mg/T

Example 2 A Method for Preparation of a Pediatric Dry Syrup of Compound(I-1)

100 g of PVP K30 was dissolved to 1600 g of purified water. Theseaqueous solution were acidified by DL-Malic acid. The compound (I-1) wasdispersed in the acidic solution under stirring. The suspension wasneutralized with 230 g of 13% NaOH aqueous solution.

A dried granule was prepared by spraying and drying the obtainedsuspension with L-8 type of spray dryer. 236 g of the granule wasblended with 743 g of powdered sugar, 15 g of xanthan gum, 4 g of sodiumbenzoate, and 2 g of a silicon resin adsorbent powder to give apediatric dry syrup.

The contents of the obtained pediatric dry syrup were shown in Table 2.

TABLE 2 The contents of a dry syrup by a spray dry method adding anacid. Compound (I-1) 200.0 Mg PVP K30 20.0 DL-malic acid 10.0 Sodiumhydroxide 6.0 Powdered sugar 743.0 Xanthan gum 15.0 Sodium benzoate 4.0Silicon resin 1.0 Aerosil 1.0 Total 1000.0 Mg

Example 3 A Method for Preparation of a Suspension of the Compound (I-1)Example 3-1 Adding Malic Acid

50 g of PVP K30 was dissolved to 800 g of purified water. These aqueoussolution were acidified by DL-Malic acid. The compound (I-1) wassuspended in the acidic solution under stirring. The suspension wasneutralized with 115 g of 13% NaOH aqueous solution to give asuspension.

Example 3-2 Adding Citric Acid

In place of malic acid in Example 3-1, citric acid was used.

Example 3-3 Adding Phosphoric Acid

In place of malic acid in Example 3-1, phosphoric acid was used.

Reference Example 3-4 Adding No Acid

No acid was used.

Example 4 A Method for Preparation of a Suspension of Pindolol

In place of the compound (I-1) in Example 3-1, pindolol was used.

Example 5 A Method for Preparation of a Suspension of Noscapine

In place of the compound (I-1) in Example 3-1, noscapine was used.

Experiment 1 (Dissolution Profile)

Dissolution profile of the tablet of the compound (I-1) obtained inExample 1 was examined. The tablet obtained in Example 1 was containedin a glass bottle and stored at 60° C. for two weeks under sealing. Theobtained sample was examined by dissolution test in Japanesepharmacopeia. The results were shown in FIG. 4.

Experiment 2 (Content/Appearance)

Content and appearance of a tablet of the compound (I-1) obtained inExample 1 were examined. The tablet obtained in Example 1 was containedin a glass bottle and stored at 60° C. for two weeks under sealing. Thetablet obtained in Example 1 was put on a glass schale and irradiated bylight of 3570Lx for 168 hours (energy of irradiation: 600,000Lx/h). Eachtablet was examined in content? test in Japanese pharmacopeia. Stabilityof appearance was measured by color analyzer (TC-180MK II, TokyoElectrics) and compared with that before treatment.

The results were shown in Table 3.

TABLE 3 Remaining rate of active ingredient/change of appearance ChangeCondition Remaining rate of appearance (ΔE) 60° C., 2 weeks, glassbottle 101.4 0.73 Irradiation (600,000 Lx/hr) 100.0 2.55Experiment 3 (Physical Stability)

Physical stability of the pediatric dry syrup of the compound (I-1)obtained in Example 2 was examined. 1000 mg of the dry syrup obtained inExample 2 was contained in 50 cc of centrifugation tube and mixed with50 ml of purified water and lightly shaken. Dispersion of the granulewas observed by the naked eye. A dispersed suspension was stored at roomtemperature for 2 days and shaken again. Dispersion of the granule wasobserved by the naked eye.

The results were shown in Table 4.

TABLE 4 Physical stability Dispersibility and suspensibility GoodRe-dispersibility (After 2 days) Good Change of appearance (After 2weeks at 60° C.) NoneExperiment 4 (Dispersibility of Active Ingredient in an AcidicSuspension Including Various Kinds of Acids)

Dispersibility of the compound (I-1) in an acidic suspension obtained inExample 3-1 to 3-4 including various kinds of acids was examined.Dispersibility was observed by the naked eyes at the time of preparationof an suspension.

The contents of a suspension and the results of the above experimentwere shown in Table 5.

TABLE 5 The contents of a suspension and dispersibility of the compound(I-1) in a suspension including various kinds of acids. Phosphoric malicacid citric acid acid No acid Compound (I-1) 500 g 500 G 500 g 500 g PVPK30 50 50 50 50 DL-malic acid 25 — — — citric acid — 8 — — Phosphoricacid — — 4 — NaOH 15 5 2.5 — Purified water 800 800 800 800 Total 1390 g1363 G 1356.5 g 1350 g Dispersibility Good Good Good Formation of drugof foams substanceExperiment 5 (Dispersibility of a Basic Compound in a Suspension)

Dispersibility of active ingredient in the suspension obtained inExample 3-1, 4 and 5 was examined in accordance with Experiment 4.

The contents of the suspension and the results of Experimet were shownin Table 6.

TABLE 6 A suspension of a basic hydrophobic compound and dispersibilityof drug substance Com- pound (I-1) Noscapine Pindolol Compound (I-1) 500g — g — g Noscapine — 500 — Pindolol — — 500 PVP K30 50 50 50 DL-malicacid 25 25 25 NaOH 15 15 15 Purified water 800 800 800 Total 1390 g 1390g 1390 g Dispersibility Good Good Good of drug substance

INDUSTRIAL APPLICABILITY

The present invention enables a basic hydrophobic medical compound to besuspended without generating foams. A suspension, therefore, can beeasily prepared. Since the suspension is neutral, the present inventionprevents pharmaceutical equipment from getting rusty. A pharmaceuticalcomposition prepared through the present invention is improved indissolution rate, suspensibility, dispersibility, stability andbioavailability.

1. A method for preparation of a pharmaceutical composition, whichcomprises a process of suspending and dispersing a basic hydrophobicmedical compound in an acidic aqueous solution, and a process ofobtaining a neutral suspension by neutralizing the obtained suspensionwith a basic aqueous solution.
 2. A method for preparation of apharmaceutical composition, which comprises a process of suspending anddispersing a basic hydrophobic medical compound in an acidic aqueoussolution, a process of obtaining a neutral suspension by neutralizingthe obtained suspension with a basic aqueous solution, and a process ofspraying and drying the suspension neutralized through said neutralizingprocess in an atmosphere at high temperature.
 3. The method forpreparation of a pharmaceutical composition according to claim 1 or 2which is carried out for the purpose of suppressing a formation of afoaming layer.
 4. The method for preparation of a pharmaceuticalcomposition according to claim 1 or 2 which is carried out for thepurpose of improving the suspensibility and dispersibility.
 5. Themethod for preparation of a pharmaceutical composition according to anyone of claims 1 or 2 wherein the acidic aqueous solution is an aqueoussolution of malic acid, citric acid or phosphoric acid.
 6. The methodfor preparation of a pharmaceutical composition according to any one ofclaims 1 or 2 wherein the basic aqueous solution is an aqueous solutionof sodium hydroxide or potassium hydroxide.
 7. The method forpreparation of a pharmaceutical composition according to any one ofclaims 1 or 2 wherein the basic hydrophobic medical compound is apyridine derivative, an imidazole derivative or an alkylaminederivative.
 8. The method for preparation of a pharmaceuticalcomposition according to any one of claims 1 or 2 wherein the basichydrophobic medical compound is5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbamate.
 9. The method for preparation of a pharmaceutical compositionaccording to any one of claims 1 or 2 wherein the pharmaceuticalcomposition is a suspension, a dry granule, a tablet or a dry syrup. 10.A pharmaceutical composition which is prepared by a method according toany one of claims 1 or 2.